Umbilical cord MSC-derived microvesicles rejuvenate aged bone marrow MSCs via deposition of PCNA and slow aging-related degeneration in mice

Stem cell senescence increases alongside the progressive functional declines that characterize human aging, and we now know that treating aged animals with young blood can confer anti-aging effects although the assumed anti-aging factors remain largely unknown. Here, we demonstrate that neonatal umbilical cord mesenchymal stem cells (UC-MSCs), one of the youngest human tissues, are an excellent source of microvesicles (UC-MVs) that contain abundant anti-aging signals. UC-MV-rejuvenated adult bone marrow MSCs (AB-MSCs) exhibited alleviated aging phenotypes and increased self-renewal capacity and telomere length. Mechanistically, UC-MVs rejuvenates AB-MSCs at least partially by transferring proliferating cell nuclear antigen (PCNA) gene into recipient AB-MSCs. When tested in therapeutic context, UC-MV-triggered rejuvenation enhances the capacities of AB-MSCs in bone formation, wound healing, and angiogenesis. We also directly intravenously injected UC-MVs into aged mice, which conferred anti-aging phenotypes including decreased bone and kidney degeneration. Our findings reveal that human UC is a rich reservoir for UC-MVs of high translational value for providing higher-quality MSCs for cell replacement therapies, and UC-MVs can be a potential tool for anti-aging intervention.